The interaction of platelets and leukocytes with vessel walls during injury repair and immune responses may create a local inflammatory condition in which active oxygen species are important components. The role of peroxides in this condition is incompletely understood, but they may modulate several inflammatory events. Peroxides at concentrations of 1 MuM in buffer are reported to impair endothelial cell function, but current data are insufficient to define the threshold for this damage by peroxide in the presence of proteins and enzymatic peroxide scavengers in biological systems. The limits for the involvement of peroxides in vascular injury also depend upon the levels of hydroperoxide in plasma during health and disease. To gain a more quantitative understanding of these limits, experiments are proposed to: determine the amount of lipid hydroperoxides in blood and the distribution of peroxide among various lipoprotein fractions; measure the response of vascular segments to hydroperoxides; and determine the ability of antiinflammatory agents to reduce blood hydroperoxides and to change vascular resistance to peroxide damage. To determine the concentrations of the peroxides in blood, a new, specific enzymatic assay will be used, and the results will be compared with those from the conventional thiobarbituric assay. Plasma lipoprotein fractions will be separated, and the peroxide concentration in each fraction will be measured. These measurements will be performed with plasma from healthy humans and patients with cardiovascular or immune-related diseases and from laboratory animals (rats, New Zealand White and Watanabe rabbits). The effect of different antioxidant and antiinflammatory agents upon the level of peroxides in plasma and on the susceptibility of the vascular tissues to the lipid peroxides will be examined. Changes in prostacyclin synthase, lactate dehydrogenase, and pyruvate kinase activities in vascular segments and subcellular fractions will be determined after challenge with different types of peroxides and different pharmacologic regimens. With the results of these experiments, the limits of the involvement of lipid hydroperoxides in vascular injury can be defined more precisely, and the need to pharmacologically modulate plasma levels of lipid hydroperoxides can be evaluated.
